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Abstract Background Purine nucleotides exhibit various functions in cellular metabolism. Besides serving as building blocks for nucleic acid synthesis, they participate in signaling pathways and energy metabolism. Further, IMP and GMP represent industrially relevant biotechnological products used as flavor enhancing additives in food industry. Therefore, this work aimed towards the accumulation of IMP applying targeted genetic engineering of Corynebacterium glutamicum. Results Blocking of the degrading reactions towards AMP and GMP lead to a 45-fold increased intracellular IMP pool of 22 μmol gCDW-1. Deletion of the pgi gene encoding glucose 6-phosphate isomerase in combination with the deactivated AMP and GMP generating reactions, however, resulted in significantly decreased IMP pools (13 μmol gCDW-1). Targeted metabolite profiling of the purine biosynthetic pathway further revealed a metabolite shift towards the formation of the corresponding nucleobase hypoxanthine (102 μmol gCDW-1) derived from IMP degradation. Conclusions The purine biosynthetic pathway is strongly interconnected with various parts of the central metabolism and therefore tightly controlled. However, deleting degrading reactions from IMP to AMP and GMP significantly increased intracellular IMP levels. Due to the complexity of this pathway further degradation from IMP to the corresponding nucleobase drastically increased suggesting additional targets for future strain optimization.

The author reflects on the work that the American Board of Phlebology is doing to promote the creation of a cross-specialty consensus-driven phlebology curriculum in medical education. He suggests that such a curriculum will benefit all medical practitioners, regardless of whether they care for patients with venous disease or not. He argues that venous disease is practically absent from medical training curricula and that a consensus-driven curriculum will address this problem.

Background: Sclerotherapy is a non-invasive procedure commonly used to treat superficial venous disease, vascular malformations and other ectatic vascular lesions. While extremely rare, sclerotherapy may be complicated by serious adverse events., Objectives: To categorise contraindications to sclerotherapy based on the available scientific evidence., Methods: An international, multi-disciplinary panel of phlebologists reviewed the available scientific evidence and developed consensus where evidence was lacking or limited., Results: Absolute Contraindications to sclerotherapy where the risk of harm would outweigh any benefits include known hypersensitivity to sclerosing agents; acute venous thromboembolism (VTE); severe neurological or cardiac adverse events complicating a previous sclerotherapy treatment; severe acute systemic illness or infection; and critical limb ischaemia. Relative Contraindications to sclerotherapy where the potential benefits of the proposed treatment would outweigh the risk of harm or the risks may be mitigated by other measures include pregnancy, postpartum and breastfeeding; hypercoagulable states with risk of VTE; risk of neurological adverse events; risk of cardiac adverse events and poorly controlled chronic systemic illness. Conditions and circumstances where Warnings and Precautions should be considered before proceeding with sclerotherapy include risk of cutaneous necrosis or cosmetic complications such as pigmentation and telangiectatic matting; intake of medications such as the oral contraceptive and other exogenous oestrogens, disulfiram and minocycline; and psychosocial factors and psychiatric comorbidities that may increase the risk of adverse events or compromise optimal treatment outcomes., Conclusions: Sclerotherapy can achieve safe clinical outcomes provided that (1) patient-related risk factors and in particular all material risks are (1a) adequately identified and the risk benefit ratio is clearly and openly discussed with treatment candidates within a reasonable timeframe prior to the actual procedure; (1b) when an individual is not a suitable candidate for the proposed intervention, conservative treatment options including the option of ' no intervention as a treatment option ' are discussed; (1c) complex cases are referred for treatment in controlled and standardised settings and by practitioners with more expertise in the field; (1d) only suitable individuals with no absolute contraindications or those with relative contraindications where the benefits outweigh the risks are offered intervention; (1e) if proceeding with intervention, appropriate prophylactic measures and other risk-mitigating strategies are adopted and appropriate follow-up is organised; and (2) procedure-related risk factors are minimised by ensuring the treating physicians (2a) have adequate training in general phlebology with additional training in duplex ultrasound, procedural phlebology and in particular sclerotherapy; (2b) maintain their knowledge and competency over time and (2c) review and optimise their treatment strategies and techniques on a regular basis to keep up with the ongoing progress in medical technology and contemporary scientific evidence.

Purpose: The current study evaluates the demographic, clinical, and neurocognitive characteristics of a recruited FEP research sample, a research control group, and a FEP clinic sample that were assessed and treated within the same center and time period., Methods: This study utilized data collected through an observational study and a retrospective chart review. Samples were ascertained in the Longitudinal Assessment and Monitoring of Clinical Status and Brain Function in Adolescents and Adults study and the Prevention and Recovery in Early Psychosis clinic. FEP clinic patients (n = 77), FEP research participants (n = 44), and age-matched controls (n = 38) were assessed using the MATRICS consensus cognitive battery and global functioning social and role scales. Between-group differences were assessed via one-way ANOVA and Chi-square analyses., Results: No significant differences were observed between groups with regard to age and gender. The FEP research sample had a higher proportion of white participants, better social and role functioning, and better neurocognitive performance when compared with the FEP clinical population. The clinic sample also had more diagnostic variability and higher prevalence of substance use disorders relative to the FEP research sample., Conclusions: Researchers should be aware of how study design and recruitment practices may impact the representativeness of samples, with particular concern for equal representation of racial minorities and patients with more severe illness. Studies should be designed to minimize burden to promote a wider range of participation.

There are excellent guidelines for clinicians to manage venous diseases but few reviews to assess their hemodynamic background. Hemodynamic concepts that evolved in the past have largely remained unchallenged in recent decades, perhaps due to their often complicated nature and in part due to emergence of new diagnostic techniques. Duplex ultrasound scanning and other imaging techniques which evolved in the latter part of the 20th century have dominated investigation. They have greatly improved our understanding of the anatomical patterns of venous reflux and obstruction. However, they do not provide the physiological basis for understanding the hemodynamics of flow, pressure, compliance and resistance. Hemodynamic investigations appear to provide a better correlation with post-treatment clinical outcome and quality of life than ultrasound findings. There is a far better prospect for understanding the complete picture of the patient's disability and response to management by combining ultrasound with hemodynamic studies. Accordingly, at the instigation of Dr Angelo Scuderi, the Union Internationale de Phlebologie (UIP) executive board commissioned a large number of experts to assess all aspects of management for venous disease by evidence-based principles. These included experts from various member societies including the European Venous Forum (EVF), American Venous Forum (AVF), American College of Phlebology (ACP) and Cardiovascular Disease Educational and Research Trust (CDERT). Their aim was to confirm or dispel long-held hemodynamic principles and to provide a comprehensive review of venous hemodynamic concepts underlying the pathophysiology of lower limb venous disorders, their usefulness for investigating patients and the relevant hemodynamic changes associated with various forms of treatment. Chapter 1 is devoted to basic hemodynamic concepts and normal venous physiology. Chapter 2 presents the mechanism and magnitude of hemodynamic changes in acute deep vein thrombosis indicating their pathophysiological and clinical significance. Chapter 3 describes the hemodynamic changes that occur in different classes of chronic venous disease and their relation to the anatomic extent of disease in the macrocirculation and microcirculation. The next four chapters (Chapters 4-7) describe the hemodynamic changes resulting from treatmen by compression using different materials, intermittent compression devices, pharmacological agents and finally surgical or endovenous ablation. Chapter 8 discusses the unique hemodynamic features associated with alternative treatment techniques used by the CHIVA and ASVAL. Chapter 9 describes the hemodynamic effects following treatment to relieve pelvic reflux and obstruction. Finally, Chapter 10 demonstrates that contrary to general belief there is a moderate to good correlation between certain hemodynamic measurements and clinical severity of chronic venous disease. The authors believe that this document will be a timely asset to both clinicians and researchers alike. It is directed towards surgeons and physicians who are anxious to incorporate the conclusions of research into their daily practice. It is also directed to postgraduate trainees, vascular technologists and bioengineers, particularly to help them understand the hemodynamic background to pathophysiology, investigations and treatment of patients with venous disorders. Hopefully it will be a platform for those who would like to embark on new research in the field of venous disease.

Background: Early intervention services for psychotic disorders optimally interlock strategies to deliver: (i) Early Detection (ED) to shorten the time between onset of psychotic symptoms and effective treatment (i.e. Duration of Untreated Psychosis, DUP); and (ii) comprehensive intervention during the subsequent 2 to 5 years. In the latter category, are teams ('First-episode Services' or FES) that integrate several empirically supported treatments and adapt their delivery to younger patients and caregivers. There is an urgent need to hasten access to established FES in the U.S. Despite improved outcomes for those in treatment, these FES routinely engage patients a year or more after psychosis onset. The Scandinavian TIPS study was able to effectively reduce DUP in a defined geographic catchment. The guiding questions for this study are: can a U.S. adaptation of the TIPS approach to ED substantially reduce DUP and improve outcomes beyond existing FES?, Methods/design: The primary aim is to determine whether ED can reduce DUP in the US, as compared to usual detection. ED will be implemented by one FES (STEP) based in southern Connecticut, and usual detection efforts will continue at a comparable FES (PREP(R)) serving the greater Boston metropolitan area. The secondary aim is to determine whether DUP reduction can improve presentation, engagement and early outcomes in FES care. A quasi-experimental design will compare the impact of ED on DUP at STEP compared to PREP(R) over 3 successive campaign years. The campaign will deploy 3 components that seek to transform pathways to care in 8 towns surrounding STEP. Social marketing approaches will inform a public education campaign to enable rapid and effective help-seeking behavior. Professional outreach and detailing to a wide variety of care providers, including those in the healthcare, educational and judicial sectors, will facilitate rapid redirection of appropriate patients to STEP. Finally, performance improvement measures within STEP will hasten engagement upon referral., Discussion: STEP-ED will test an ED campaign adapted to heterogeneous U.S. pathways to care while also improving our understanding of these pathways and their impact on early outcomes., Trial Registration: ClinicalTrials.gov: NCT02069925 . Registered 20 February 2014.

Background: Compression bandages appear to be simple medical devices. However, there is a lack of agreement over their classification and confusion over the use of important terms such as elastic, inelastic, and stiffness., Objectives: The objectives were to propose terms to describe both simple and complex compression bandage systems and to offer classification based on in vivo measurements of subbandage pressure and stiffness., Methods: A consensus meeting of experts including members from medical professions and from companies producing compression products discussed a proposal that was sent out beforehand and agreed on by the authors after correction., Results: Pressure, layers, components, and elastic properties (P-LA-C-E) are the important characteristics of compression bandages. Based on simple in vivo measurements, pressure ranges and elastic properties of different bandage systems can be described. Descriptions of composite bandages should also report the number of layers of bandage material applied to the leg and the components that have been used to create the final bandage system., Conclusion: Future descriptions of compression bandages should include the subbandage pressure range measured in the medial gaiter area, the number of layers, and a specification of the bandage components and of the elastic property (stiffness) of the final bandage.

Background: Chronic venous disorders (CVD) have an impact on quality of life (QoL), both physically and psychologically. As of now, several vein specific QoL scales exist, but no patient-reported outcome (PRO) is available which takes into account altogether symptoms, impairment of activities, appearance of the legs and concerns regarding health risk. Since clinical severity and disability are mostly evaluated in severe patients, where the main outcome - namely skin changes - is obvious but rare, the authors considered that a reproducible and clinically relevant survey that could account for specific patients' complaints was needed, particularly for CEAP C0s-C3 patients., Objectives: The objective of this study was to build a specific autoquestionnaire and to establish its statistical validity and clinical relevance., Methods: A review of existing questionnaires and an analysis of relevant literature were carried out by a committee of experts. The committee then developed a questionnaire of 46 items, with special attention to relevance for venous disorders and patients' main complaints. After construction, the French version was field-tested and results statistically analyzed. In the specific QoL & Outcome Response - Venous (SQOR-V), each item is given a value by the patient and items are grouped in five dimensions. Each dimension is weighed to a maximum value of 20, yielding an overall maximum score of 100., Results: Two hundred and two questionnaires were analyzed for the initial evaluation and 152 at a second (test-retest). Determination of the Cronbach's alpha coefficient (0.96) and structural analysis demonstrated an excellent internal and structural coherence. Test-retest comparisons confirmed good reproducibility. Comparison with SF-12 and CED-D questionnaires and with CEAP classification groups verified both structural and clinical validity., Conclusions: This study demonstrates QoL impairment in patients suffering from chronic venous disorders (CVD). It also verifies the statistical validity of the SQOR-V questionnaire. More studies are needed to demonstrate the improvement in specificity and accuracy this questionnaire provides compared to existing vein-specific QoL scales, and to determine its ability to assess efficacy of any kind of treatment at any stage of the disease. Provided adequate acknowledgment of its authors, the use of SQOR-V is free. An English version is available, currently pending validation.

Purpose: To assess the safety and preliminary efficacy of endovenous laser treatment (EVLT), a novel percutaneous technique for occlusion of the incompetent greater saphenous vein (GSV)., Materials and Methods: Ninety GSVs in 84 patients with reflux at the saphenofemoral junction (SFJ) into the GSV were treated endovenously with pulses of laser energy and evaluated in a prospective, nonrandomized, consecutive enrollment multicenter study. Patients were evaluated at 1 week and at 1, 3, 6, and 9 months to determine efficacy and complications., Results: Eighty-seven of 90 GSVs (97%) were closed 1 week after initial treatment with endovenous laser. The remaining three GSVs were closed after repeat treatment. Eighty-nine of 90 GSVs (99%) remained closed for as long as 9 months according to serial duplex ultrasonography. Sonographic evaluation demonstrated 73% reduction in GSV diameter at 6 months (61 patients) and 81% reduction in GSV diameter at 9 months (26 patients) after EVLT. One patient developed a transient localized skin paresthesia. There have been no other minor or major complications., Conclusions: EVLT of the incompetent GSV appears to be an extremely safe technique that yields impressive short-term results. Long-term follow-up is awaited.

Substance use disorders, particularly those involving alcohol, marijuana, and cocaine, are highly prevalent among patients with schizophrenia and contribute markedly to its overall morbidity. Unfortunately, standard (typical) antipsychotic medications do not seem to reduce substance use in patients with schizophrenia and may even increase it. Recently, however, a few anecdotal case reports and two previous small "N" surveys have found that clozapine, an atypical antipsychotic medication, seems to decrease substance use in patients treated with this drug for their psychoses. The authors report data from a retrospective survey of substance use in 58 patients treated with clozapine who had a history of comorbid schizophrenia (or schizoaffective disorder) and substance use disorder. Of these 58 patients, 43 were being treated with clozapine at the time of the survey; the remaining 15 patients had discontinued clozapine before the survey. The survey involved chart review and clinician interview to assess change in substance use and global clinical symptoms while receiving treatment with clozapine. More than 85% of the patients who were active substance users at the time of initiation of treatment with clozapine decreased their substance use over the course of clozapine administration. For patients who continued treatment with clozapine up to the present, the decrease in substance use was strongly correlated with a decrease in global clinical symptoms. Data from this retrospective survey further support the previous observations that clozapine reduces substance use among patients with schizophrenic disorders. Moreover, the data suggest the need for prospective controlled studies of the effects of clozapine on substance use in this population.

Background: Venous leg ulcers are common in the adult population and cause a significant social economic burden. Despite their prevalence, venous leg ulcers are often managed inadequately., Objective: To provide an overview of venous ulceration, including a review of the current understanding of the pathophysiology of venous ulceration and the implications for management of venous ulceration., Methods: A review of the literature., Results: Modern methods of investigation have led to an improvement in our understanding of the pathophysiology of venous disease. In many patients, superficial and/or perforator venous disease is the only underlying hemodynamic abnormality. Although compression should serve as the cornerstone of treatment of venous ulceration, surgery and/or sclerotherapy can treat incompetent superficial and perforator veins. Important hemodynamic improvement is obtained, and the long-term prognosis of these patients is greatly improved., Conclusion: One must define the basic underlying abnormality of the venous system to form a rational, individualized management plan for the patient with venous ulceration.

Alcohol and other drugs of abuse are commonly used by persons with schizophrenia and contribute to the overall morbidity of the disorder. Standard, or typical, antipsychotic drugs do not limit such substance use and may even render it more likely. However, preliminary data from our group and others suggest that the atypical antipsychotic clozapine may decrease substance use in this population. While recognizing the likelihood that substance use decreases negative symptoms (as well as extrapyramidal symptoms) in persons with schizophrenia, we hypothesize that the biological basis of substance use relates to a "reward-deficiency syndrome" secondary to dysfunctional dopamine-mediated mesocorticolimbic neurons in these individuals. We further suggest that clozapine's beneficial effect in patients with comorbid schizophrenia and substance use disorders may relate to its presumed ability to ameliorate the deficits in both the mesocortical and mesolimbic dopaminergic neuronal projections through its various actions on dopaminergic, serotonergic, and particularly noradrenergic neurons.

Background: A previous study found hyaluronidase to be effective in the prevention of necrosis following intradermal sodium tetradecyl sulfate and 23.4% sodium chloride. There are no published dose-response studies of hyaluronidase used in this manner., Objective: To conduct a dose-response study using hyaluronidase in the prevention of necrosis following intradermal 23.4% sodium chloride., Methods: Study I evaluated control vs hyaluronidase groups (150, 300, 450 units; all in volume of 3 mL) in the prevention of necrosis following intradermal 0.25 mL 23.4% sodium chloride. Incidence and size of necrosis were compared between groups. In study II, hyaluronidase was administered in doses ranging from 18.75 to 900 units (all in volume of 3 mL) immediately following the intradermal instillation of 0.25 mL of 23.4% sodium chloride. A control group had no therapy. The incidence of necrosis was compared between groups. A dose-response curve was constructed. Both studies were randomized and blinded and used Sprague-Dawley rats., Results: A statistically significant protective effect was found in the treated vs the untreated groups in both studies. Maximal protection was achieved by 75 units of hyaluronidase and was not improved upon by higher doses., Conclusion: In the event of extravasation with 23.4% sodium chloride, in the model studied, one can expect maximal protection with a dose of 75 units of hyaluronidase.

Background: Most authors have recommended treating extravasation during sclerotherapy by infiltrating the area with 0.9% sodium chloride and/or procaine., Objective: To evaluate interventions in the prevention of necrosis following intradermal injection of 23.4% sodium chloride and 3% sodium tetradecyl sulfate., Methods: Following intradermal 23.4% sodium chloride (Study I) or 3% sodium tetradecyl sulfate (Study II), subjects (Sprague-Dawley rats) received either no treatment or injections of 0.9% sodium chloride, sterile water, 1% procaine, or hyaluronidase. Groups were compared regarding incidence and size of necrosis., Results: In study I, hyaluronidase treated groups had significantly fewer and smaller areas of necrosis than other groups. In study II, the hyaluronidase group developed significantly fewer ulcers than the 0.9% sodium chloride group. The 0.9% sodium chloride group had significantly larger ulcers than other groups., Conclusion: In the model studied, hyaluronidase was the only effective treatment in the prevention of necrosis. Following 3% sodium tetradecyl sulfate, 0.9% sodium chloride was associated with larger ulcers than other groups.

Alveolar macrophages were obtained from human volunteers, smokers and nonsmokers, by bronchial lavage through a fiberoptic bronchoscope. Cells were incubated in a chemically defined medium containing [(14)C]sucrose (0.36 mM) and varying concentrations of rabbit serum. Pinocytosis was assessed by the cellular uptake of isotope over 30, 75, and 120-min periods. Pinocytic activity of smokers' cells was dependent on serum concentration but always less than the activity of nonsmokers' cells. The degree of pinocytosis by nonsmokers' cells was independent of serum concentration. It is concluded that the decreased level of pinocytic activity in smokers' alveolar macrophages as indicated by the uptake of sucrose in the presence of rabbit serum may represent a form of reticuloendothelial blockade.

The ontogeny of single nephron filtration distribution was studied in 29 canine puppies two hr to 42 days old using the [14C] ferrocyanide method as modified by Coehlo (9). The ratio of 14C counts in outer cortical nephrons (OC) to counts in juxtamedullary nephrons (JM) were plotted against age for each puppy. This ratio (OC:JM) provided an index for comparing the single nephron glomerular filtration between regions. A four-fold increase in OC:JM occurred from two days to four wk. The youngest puppy, two hr old, showed a ratio of zero because no counts were detected in OC at that age. The most rapid increase occurred in the first 8 days of life. By the fourth wk, the mean OC:JM ratio was 0.72 +/- 0.06, approaching values reported by other laboratories for adult dogs. In contrast to age-related changes in OC:JM ratio, the ratio of middle cortical to JM counts showed no age-related increase. Cortical blood flow distribution was determined by the microsphere method. The ratio of blood flow to outer and inner cortex increased from 0.43 at one-half a day to a mean of 2.93 after one wk. The ratio of OC:JM single nephron filtration of OC/inner cortical nephron renal blood flow was 0.36 from 3 days to 26 days (n = 12) and did not change significantly with age, indicating that changes in zonal filtraion matched the alterations in cortical blood flow distribution.

Pleural involvement has generally been considered an unusual aspect of sarcoidosis. In this paper, five previously unreported cases of sarcoidosis involving the pleura were discussed. Pleural sarcoidosis may be manifested by the presence of a pleural effusion, and the diagnosis is based on the exclusion of all other possible causes and the demonstration of noncaseating granulomas in the pleura. When the pleura is involved without effusion, it may only be recognized if noncaseating granulomas involving the pleura are looked for specifically. Including the five cases form this study, there have been 73 cases of pleural sarcoidosis reported, but only 37 have been verified by histologic evidence. When strict diagnostic criteria are used, clinical involvement of the pleura in sarsoidosis remains an unusual entity, but it may be that histologic involvement of the pleura is more common than generally appreciated.